Developmental brain abnormalities and acute encephalopathy in a patient with myopathy with extrapyramidal signs
Katelynn M Wilton1, Joel A Morales-Rosado2,3, Duygu Selcen4
1Medical Scientist Training Program, Mayo Clinic Alix College of Medicine Mayo Clinic Rochester Minnesota USA.
Abstract:
Mitochondria play a variety of roles in the cell, far beyond their widely recognized role in ATP generation. One such role is the regulation and sequestration of calcium, which is done with the help of the mitochondrial calcium uniporter (MCU) and its regulators, MICU1 and MICU2. Genetic variations in MICU1 and MICU2 have been reported to cause myopathy, developmental disability and neurological symptoms typical of mitochondrial disorders. The symptoms of MICU1/2 deficiency have generally been attributed to calcium regulation in the metabolic and biochemical roles of mitochondria. Here, we report a female child with heterozygous MICU1 variants and multiple congenital brain malformations on MRI. Specifically, she shows anterior perisylvian polymicrogyria, dysmorphic basal ganglia, and cerebellar dysplasia in addition to white matter abnormalities. These novel findings suggest that MICU1 is necessary for proper neurodevelopment through a variety of potential mechanisms, including calcium-mediated regulation of the neuronal cytoskeleton, Miro1-MCU complex-mediated mitochondrial movement, or enhancing ATP production. This case provides new insight into the molecular pathogenesis of MCU dysfunction and may represent a novel diagnostic feature of calcium-based mitochondrial disease.
Insights
Mitochondrial calcium regulators MICU1 and MICU2 are crucial for brain development. Genetic variants in MICU1 cause congenital brain malformations, revealing new insights into mitochondrial disease pathogenesis.
Area of Science:
- Cell Biology
- Neuroscience
- Genetics
Background:
- Mitochondria regulate cellular calcium (Ca2+) homeostasis via the mitochondrial calcium uniporter (MCU) and its regulators MICU1 and MICU2.
- Genetic variations in MICU1/MICU2 are linked to myopathy, developmental delays, and neurological symptoms characteristic of mitochondrial disorders.
- Previous understanding attributed MICU1/2 deficiency symptoms to impaired calcium regulation in mitochondrial metabolic functions.
Observation:
- A female infant with heterozygous MICU1 variants presented with multiple congenital brain malformations on MRI.
- Specific malformations included anterior perisylvian polymicrogyria, dysmorphic basal ganglia, cerebellar dysplasia, and white matter abnormalities.
- This case highlights a novel association between MICU1 variants and complex neurodevelopmental defects.
Findings:
- MICU1 variants are associated with significant congenital brain malformations.
- These findings suggest MICU1 plays a critical role in neurodevelopment beyond its known functions in cellular metabolism.
- Potential mechanisms include calcium-mediated cytoskeletal regulation, mitochondrial dynamics, and ATP production.
Implications:
- This study expands the known phenotypic spectrum of MICU1-related disorders.
- It suggests MICU1 is essential for normal human brain development.
- The findings may represent a novel diagnostic feature for calcium-related mitochondrial diseases affecting the brain.
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